Growth promoters for animals

ABSTRACT

A delivery system for providing growth promoters to food animals is provided and a method of promoting growth in food animals using such delivery systems is described.

This application is a continuation of application Ser. No. 07/523,249,filed May 15, 1990, now U.S. Pat. No. 5,288,496.

FIELD OF THE INVENTION

This invention is directed to a delivery system which may be used toprovide growth promoters for animals.

BACKGROUND OF THE INVENTION

Recent advances in pharmaceutical bioengineering have stimulated theinterest of the food industry in new delivery systems for hormones andother growth promoters.

Steroids, and especially anabolic steroids, are widely used to promotethe growth of cattle and other food animals. Such growth promotion isdesirable among food producers because it maximizes the weight gain peranimal per amount of food consumed.

Currently, steroid products are usually supplied to the animal in theform of a non-biodegradable, implantable steroid time-release pelletwhich is placed in the ear skin, part of the animal which is discardedupon slaughter. Such delivery systems have been recently reviewed(Sawyer, G. J., et al., Austral. Vet. J. 65: 101-108 (1988). The pelletsystems cannot provide a pulsed dose of steroid and are oftenreimplanted two or three times throughout the life of the animal witheach implant being administered by a specially designed injector gun.

The use of pellet delivery systems has not met with complete success andthey have many disadvantages. The main health concern is that misuse ofthe non-degradable pellet system may result in harmful levels of suchsteroids in the meat provided to consumers. Such misuse may arise if thepellet is misplaced. For example, if the pellet is misplaced in the neckor behind the ear instead of in the ear skin, the possibility is raisedthat the remains of the pellet could be ingested by the consumer. Also,a farmer may mistakenly inject more than one pellet at a time. Also, thepellets are often not successfully implanted and fall to the ground inthe treatment pen.

Disadvantages of the currently available pellet implants further includetheir inability to allow for combination of different drugs with highlycontrolled release rates in the same unit, and the fact that only 40-70%of the active agent is released. Lastly, commercial implants do notoffer a capability in adjusting the duration of action and because ofthe nondegradable polymeric excipient and the relatively low totalsurface area of the pellets, it is very difficult to adjust the dosageof the active agent.

Compudose^(R) is a polymeric controlled release implant device for usewith beef cattle which is designed to provide for the continuousdelivery of estradiol-17β for 200 or 400 days (Ferguson, T. H. et al.,J. Cont. Rel 8: 45-54 (1988)). The compudose^(R) implant is made bycoating a nonmedicated silicone rubber core with a thin layer ofsilicone runner which contains micronized crystalline estradiol-17β.However, the device is not biodegradable.

Biodegradable particles for use in the delivery of steroid hormones havebeen described (U.S. Pat. No. 4,329,331, U.S. Pat. No. 4,489,055, U.S.Pat. No. 4,683,288, U.S. Pat. No. 4,677,191, U.S. Pat. No. 4,675,189,U.S. Pat. No. 4,530,840, U.S. Pat. No. 4,542,025 and U.S. Pat. No.4,389,330.

However, none of the above references have suggested or disclosed amethod of increasing animal growth by providing a biodegradablemicroparticle delivery of steroid growth promoters in food animals and aneed exists for better, safer delivery systems for steroids in foodanimals.

SUMMARY OF THE INVENTION

With the above-described needs in mind, the present inventor set out todevelop a composition which could be adapted to accomplish the sustainedrelease of steroid growth promoters in food animals in a manner whichwould not only more efficiently promote the growth of such animals butwhich would also provide a safer delivery system for the growthpromoting compounds.

The invention further provides a method of delivering growth promotersto animals in a multiphasic manner.

The invention further provides a method of delivering two or more activeagents at predetermined release rates with the release of each drugbeing at a different rate and duration by design.

In detail, the invention provides a method of stimulating growth in ananimal by treating such animals with injectable, biodegradablemicroparticles, wherein such microparticles are loaded with at least onegrowth-promoting steroid. Populations of microparticles with differentactive steroids or other types of bioactive agents, such as antibioticsor vaccines can be blended to form a composite formulation.

In one embodiment, the growth-promoting steroid is selected from thegroup consisting of estradiol benzoate, 17β-estradiol, trenboloneacetate, zeranol, testosterone and testosterone derivatives orcombinations thereof.

The invention further concerns the embodiment of the above-describedmethod wherein the biodegradable microparticles comprise a homopolymeror copolymer of lactic/glycolic acid, polycaprolactone, polydioxonone,polyorthoesters, polyanhydides, and natural polymers including albumin,casein, and waxes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 graphically presents the data from Table III.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In order to provide a clearer and consistent understanding of thespecification and claims, including the scope to be given such terms,the following definitions are provided.

By the term "administered" is intended any method of delivering thegrowth promoting microparticles of the invention to an animal, such as,for example, parenteral (intravenous, intramuscular, or subcutaneous)administration.

By the term "food animal" is intended any animal that is consumed as asource of protein in the diet of humans or other animals. Typical foodanimals include bovine animals, for example cattle; ovine animals, forexample sheep; porcine, for example pigs; fowl, for example chickens andturkeys; rabbit, and the like.

By "promoting growth" or "increasing growth" is meant increasing theweight or weight gain of an animal by an amount not found in an animalwhose growth was not being "promoted."

By "microparticles" is meant solid particles which contain an activeagent, herein a growth promoting metabolic steroid, either in solutionor in crystalline form. The active agent is dispersed or dissolvedwithin the polymer which serves as the matrix of the particle.

The present invention concerns a method of increasing growth in foodanimals which comprises providing to such animals biodegradablemicroparticles loaded with a metabolic steroid. The method of thepresent invention provides advantages over methods known in the art suchas, inter alia, an increased weight gain, a biodegradable system, aninjectable system which prevents the loss of dose during treatment whichoften occurs with solid pellet implants, the ability to mixmicroparticles containing different drugs, the ability to programrelease (multiphasic release patterns) to give faster rates of drugrelease as the animal grows larger, and the ability to stimulate growthin poultry.

Further, the method of the invention provides the ability to design aunique blood hormone profile for the animal and a multiphasic hormonedelivery system which provides pulsed doses of desired growth promoter,thus eliminating a need for consecutive implant treatments.

The product of the present invention offers the advantage of durationsof action ranging from only 30 to 60 days to more than 200 daysdepending upon the type of microsphere selected. In the preferredembodiment the microspheres are designed to afford growth promotion inanimals over a period of 150 to 250 days. The duration of action can beeasily controlled by manipulation of the polymer composition,polymer:drug ratio and microsphere size.

Another important advantage of the present invention is that practicallyall of the active drug is delivered to the animal whereas with existingcommercial implants only 40 to 75% of the active agent is released.Because the polymer used in the method of the invention isbiodegradable, all of the entrapped drug can be released into theanimal.

The preferred construction of microparticles of the invention aredescribed in U.S. Pat. No. 4,389,330, and U.S. Pat. No. 4,530,840, fullyincorporated herein by reference. The microparticles of the inventionare composed of a polymer which is, preferably, either a homopolymer orcopolymer of lactic or glycolic acids. Other bio-degradable polymers maybe used, such as, for example, polycaprolactone, polydioxonene,polyorthoesters, polyanhydides, and natural polymers including albumin,casein, and waxes.

The present invention is directed to a method of stimulating growth infood animals by administering an injectable, long-acting biodegradablemicroparticle which contains a growth promoter for food animals.Suitable growth promoters include 17β-estradiol, estradiol benzoate,trenbolone acetate, zeranol, testosterone, testosterone derivatives (andespecially testosterone propionate) and any combination thereof.

In a preferred embodiment, administration of the growth promoter to foodanimals by the method of the invention is achieved by a singleadministration of the growth promoter loaded microparticles and themicroparticles release the active growth promoter in a constant orpulsed manner into the animal and eliminates the need for repetitiveinjections.

The formulation of the present invention contains a growth promoterdispersed in a microparticle matrix material. The amount of growthpromoter agent incorporated in the microparticles usually ranges fromless than 1 wt % to as high as 95 wt. %, preferably 10 to 50 wt. %. Byweight % is meant parts of drug per parts of polymer by weight. Forexample, 10 wt. % would mean 10 parts drug per 90 parts polymer byweight.

The polymeric matrix material of the microparticles present inventionmust be a biocompatible and biodegradable polymeric material. The termbiocompatible is defined as a polymeric material which is not toxic toan animal and not carcinogenic. The matrix material should bebiodegradable in the sense that the polymeric material should degrade bybodily processes to products readily disposable by the body and shouldnot accumulate in the body. The biodegraded products also should bebiocompatible with the body in the sense that the polymeric matrix iscompatible with the body. Suitable examples of polymeric matrixmaterials include poly (glycolic acid), poly(-d,l-lactic) acid,poly(l-lactic acid) and copolymers thereof, copolyoxalates,polycaprolactone, poly (lactic acid-caprolactone), and the like.Suitable polymeric materials also include waxes such as glycerol mono-and distearate and casein.

The molecular weight of the polymeric matrix material is of someimportance. The molecular weight should be high enough so that it formssatisfactory polymer coatings, i.e., the polymer should be a good filmformer. Usually, a satisfactory molecular weight is greater than 5,000daltons. However, since the properties of the film are also partiallydependent on the particular polymeric material being used, it is verydifficult to specify an appropriate molecular weight range for allpolymers. The molecular weight of a polymer is also important from thepoint of view that molecular weight influences the biodegradation rateof the polymer. For a diffusional mechanism of drug release, the polymershould remain intact until all of the drug is released form themicroparticles and then degrade. The drug can also be released from themicroparticles as the polymeric excipient bioerodes. By an appropriateselection of polymeric materials a microparticle formulation can be madesuch that the resulting microparticles exhibit both diffusional releaseand biodegradation release properties. This is useful in affordingmultiphasic release patterns.

The microparticle product of the present invention can be prepared byany method which is capable of producing microparticles in a size rangeacceptable for use in an injectable composition. A preferred method ofpreparation is the method described in U.S. Pat. No. 4,389,330. In thismethod the desired growth promoting compound is dissolved or dispersedin an appropriate solvent. To the growth promoting agent-containingmedium is added the polymeric matrix material in an amount relative tothe active ingredient which gives a product of the desired loading ofactive agent. Optionally, all of the ingredients of the microparticleproduct can be blended in the solvent medium together. Suitable solventsfor the growth promoter compound and the polymeric matrix materialinclude organic solvents such as acetone, halogenated hydrocarbons suchas chloroform, methylene chloride and the like, aromatic hydrocarboncompounds, halogenated aromatic hydrocarbon compounds, cyclic ethers,alcohols, ethyl acetate and the like. Preferred solvents for the growthpromoter agent are methylene chloride or ethyl acetate.

The mixture of ingredients in the solvent is emulsified in acontinuous-phase processing medium; the continuous-phase medium beingsuch that a dispersion of microdroplets containing the indicatedingredients is formed in the continuous-phase medium. Naturally, thecontinuous-phase processing medium and the organic solvent must beimmiscible, and most commonly is water although nonaqueous media such asxylene and toluene and synthetic oils and natural oils can be used.Usually, a surfactant is added to the continuous-phase processing mediumto prevent the microparticles from agglomerating and to control the sizeof the solvent microdroplets in the emulsion. A preferredsurfactant-dispersing medium combination is a 1 to 10 wt. % poly (vinylalcohol) in water mixture. The dispersion is formed by mechanicalagitation of the mixed materials. An emulsion can also be formed byadding small drops of the active agent-wall forming material solution tothe continuous phase processing medium. The temperature during theformation of the emulsion is not especially critical but can influencethe size and quality of the microparticles and the solubility of thedrug in the continuous phase. Of course, it is desirable to have aslittle of the drug in the continuous phase as possible. Moreover,depending on the solvent and continuous-phase processing mediumemployed, the temperature must not be too low or the solvent andprocessing medium will solidify or the processing medium will become tooviscous for practical purposes, or too high that the processing mediumwill evaporate, or that the liquid processing medium will not bemaintained. Moreover, the temperature of the medium cannot be so highthat the stability of the particular active agent being incorporated inthe microparticles is adversely affected. Accordingly, the dispersionprocess can be conducted at any temperature which maintains stableoperating conditions, which preferred temperature being about 30° C. to60° C., depending upon the drug and excipient selected.

The dispersion which is formed is a stable emulsion and from thisdispersion the organic solvent immiscible fluid can be partially removedin the first step of the solvent removal process. The solvent can easilybe removed by common techniques such as heating, the application of areduced pressure or a combination of both. The temperature employed toevaporate solvent from the microdroplets is not critical, but should notbe that high that it degrades the growth promoting agent employed in thepreparation of a given microparticle, nor should it be so high as toevaporate solvent at such a rapid rate to cause defects in the wallforming material. Generally, from 5 to 75%, preferably 1 to 25% of thesolvent is removed in the first solvent removal step.

After the first stage, the dispersed microparticles in the solventimmiscible fluid medium are isolated from the fluid medium by anyconvenient means of separation. Thus, for example, the fluid can bedecanted from the microparticle or the microparticle suspension can befiltered. Still other, various combinations of separation techniques canbe used if desired.

Following the isolation of the microparticles from the continuous-phaseprocessing medium, the remainder of the solvent in the microparticles isremoved by extraction. In this step, the microparticles can be suspendedin the same continuous-phase processing medium used in step one, with orwithout surfactant, or in another liquid. The extraction medium removesthe solvent from the microparticles and yet does not dissolve themicroparticles. During the extraction, the extraction medium withdissolved solvent must be removed and replaced with fresh extractionmedium. This is best done on a continual basis, where the rate ofextraction medium replenishment is critical. If the rate is too slow,agent crystals will protrude from the microparticles or grow in theextraction medium. Obviously, the rate of extraction mediumreplenishment or a given process is a variable which can easily bedetermined at the time the process is performed and, therefore, noprecise limits for the rate must be predetermined. After the majority ofthe solvent has been removed from the microparticles, the microparticlesare dried by exposure to air or by other conventional drying techniquessuch as vacuum drying, drying over a desiccant, or the like. Thisprocess is very efficient in encapsulating the growth promoting agentsince core loadings of up to 80 wt. %, preferably up to 50 wt. % areobtained.

The microparticle product of the present invention is usually made up ofparticles of a spherical shape although sometimes the microparticles maybe irregularly shaped. The microparticles can vary in size, ranging fromsubmicron to millimeter diameters. Preferably, submicron to 250 μm, aredesirable for growth promoter formulations allowing administration ofthe microparticles with a standard gauge needle.

The growth promoting agent bearing microparticles are obtained andstored as a dry material. Prior to administration to an animal or groupof animals, the microparticles are suspended in an acceptablepharmaceutical liquid vehicle, and then the suspension is injected intothe desired portion of the body of the animal.

The amount of growth promoting agent administered to the animal dependson the particular animal species, growth promoting agent, length of timeof treatment, age of the animal and amount of growth promotion which isdesired. Since the present invention is concerned with a unique methodof promoting growth in food animals by administering growth promoters ina biodegradable microparticle formulation involving encapsulated growthpromoting agents, one skilled in the art is well aware of the dosagesrequired to treat a particular animal with a particular growth promoter.Commonly, growth promoters are administered in microgram to milligramamounts, depending upon the size of the animal and the length oftreatment time.

The microparticles can be mixed by size or by type so as to provide fora delivery of growth promoters to animals in a multiphasic manner and/orin a manner which provides different growth promoters to the animal atdifferent times, or a mixture of growth promoters to the animal at thesame time. Other biologically active agents commonly administered toanimals may be blended with the growth promoter formulation. Forexample, antibiotics, anthelmintics, vaccines, or any desired activeagent, either in microparticle form or in conventional, unencapsulatedform may be blended with the growth promoter and provided to an animalby the method of the invention.

For example, the method of the invention may also be used to deliver avaccine containing antigenic material such as an antigen or mixture ofantigens of bacterial, viral, or cellular origin. Especially, forexample, the method of the invention may be used to deliver Pasteurellamultocide, Pasteurella haemolytica, Haemophilus influenzae, Hemophilusducreyi, Escherichia coli, Salmonella abortus ovis, and IBR-BVD-PI3virus antigen(s) and vaccines.

The following examples further describe the materials and methods usedin carrying out the invention. The examples are not intended to limitthe invention in any manner.

EXAMPLES Example 1 Preparation of 20%-Loaded Estradiol BenzoateMicroparticles

This example describes the preparation of 20% loaded estradiol benzoatemicroparticles with an 85:15 poly(d,l-lactide-co-glycolide) (PLGA)excipient.

To prepare a 150 g batch of 20% loaded estradiol benzoatemicroparticles, 30 g estradiol benzoate is dissolved in 706.06 g of 17%sterile-filtered 85:15 dl-PLGA (MW=135,964)/ethyl acetate solution.During dissolution, the contents of the Erlenmeyer flask are maintainedat 60° C. Once the drug has totally dissolved, the drug/polymer solutionis added to a 3000-ml jacketed reactor containing 144 g of 3% PVA havingbeen saturated with 183 g of ethyl acetate stirring at 245 rpm at 55° C.

Once the embryonic microparticles have stabilized, the contents of thereaction flask are transferred to 110 liters of water stirring in two60-liter stainless-steel beakers at 8° C. After having been stirred inthe initial wash for 17 minutes, the hardened microparticles are wetsieved onto a 25-micron sieve. The retained product is a transferred toa second water wash of 50 liters stirring in a 60-liter stainless steelbeaker at 8° C. After having been in the second wash for 15 minutes, themicroparticles are again sieved onto a 25-micron sieve. The retainedproduct is transferred to a third and final wash of 50 liters stirringat 8° C. After stirring in the third wash for about 4 hours, product isisolated by sieving through a sieve stack composed of 25, 45, 90 and 150micron openings.

Each sieve is washed with liberal portions of fresh water and theproduct is allowed to air dry.

Example 2 Preparation of 15%-Loaded Estradiol Benzoate Microparticles

This example describes the preparation of 15% loaded estradiol benzoatemicroparticles with poly (d,l-lactide) excipient.

To prepare a 10 g batch of 15%-loaded estradiol benzoate microparticles,1.5 g estradiol benzoate and 8.6 g dl-PLA, is dissolved in 35.7 g ofethyl acetate in an Erlenmeyer flask at 52° C. The drug/polymer solutionis added to a 300-ml jacketed reaction flask containing 196 g of 3%aqueous polyvinyl alcohol having been saturated with 15.6 g of ethylacetate stirring at 570 rpm at 52° C.

Once the embryonic microparticles have stabilized, the contents of thereaction flask are transferred to 8 liters of water stirring in 10-literstainless steel beaker at 11° C. After stirring in the initial wash forapproximately 4 minutes, the hardened microparticles are wet sieved ontoa 25-micron sieve. Retained product is transferred to a second wash of 4liters stirring at 11° C. After the product has stirred in the secondwash for 6 hours, it is isolated by sieving through a sieve stackcomposed of 25, 45, 90, 150, and 212 micron openings. Each sieve iswashed with liberal portions of fresh water to more effectively separatethe different sizes of microparticles, and the product is allowed to airdry on sieves overnight.

Example 3 Preparation of 17β-Estradiol Microspheres

A 10-gram batch of 20%-loaded 17β-estradiol microspheres was prepared byweighing 8 g dl-PLA and 2 g 17β-estradiol into a 150 ml Erlenmeyerflask. Then 72 g of chloroform was added to 150 ml Erlenmeyer flask.Then 72 g of chloroform was added to the flask to dissolve the polymer.After the polymer was completely dissolved, 24 g of acetone was added todissolve the drug. The flask was maintained at 56° C. during thedrug/polymer dissolution stage. The solution was added to a 350 mljacketed resin kettle containing 215 g of 5% polyvinyl alcohol stirringat 390 rpm and maintained at 56° C. After 4 minutes, the emulsion hadstabilized and the soft microspheres were in the desired size range, thereactor contents were transferred into 8 liters of stirring water at 16°C. The microspheres were then sieved from the wash by a 25-micron sieveand the retained product was transferred into a second 8 liter stirringwash at 16° C. After stirring the product in the second wash for 3hours, the particles were isolated by sieving through an 8 inch sievestack composed of 25, 90, and 212 micron mesh. Each sieve was washedwith liberal portions of fresh water to effectively separate thedifferent sizes of microspheres. After air drying overnight, the productwas collected, weighed and placed under ambient temperature vacuum todry.

Example 4 Preparation of 50%-Loaded Trenbolone Acetate Microparticles

This example describes the preparation of 50%-loaded trenbolone acetatemicroparticles with an 85:15 poly (d,l-lactide-co-glycolide) excipient.

To prepare a 50 g batch of 50%-loaded trenbolone acetate microparticles,25 g of trenbolone acetate and 25 g of 85:15 dl-PLGA (MW=135,964), aredissolved in 110 g of ethyl acetate in an Erlenmeyer flask at 52° C. Thedrug/polymer solution is added to a 1000-ml jacketed reaction flaskcontaining about 400 g of 3% aqueous polyvinyl alcohol having beensaturated with 23 g of ethyl acetate stirring at 340 rpm at 52° C.

Once the embryonic microparticles have stabilized, the contents of thereaction flask are transferred to 45 liters of water stirring in a60-liter stainless steel beaker at 11° C. After having stirred in theinitial wash for approximately 10 minutes, the hardened microparticlesare wet sieved onto a 25-micron sieve. The product retained by the sieveis transferred to a second wash volume of 40 liters of water stirring at11° C. After 5 hours stirring in second wash, the microparticles areisolated by sieving through a sieve stack composed of 25, 90, 150, 212and 500 micron openings. Each sieve is washed with liberal portions offresh water to more effectively separate the different sizes ofmicroparticles and the product is allowed to air dry on sievesovernight.

Example 5 Preparation of 30%-Loaded Trenbolone Acetate Microparticles

This example describes the preparation of 30%-loaded trenbolone acetatemicroparticles with an 85:15 poly (d,l-lactide-co-glycolide) excipient.

To prepare a 60 g batch of 30%-loaded trenbolone acetate microparticles,18 g of trenbolone acetate and 42 g of 85:15 dl-PLGA (MW=135,964) aredissolved in 161 g of ethyl acetate in an Erlenmeyer flask at 82° C. Thedrug/polymer solution is added to a 1000-ml jacketed reaction flaskcontaining about 585 g 3% aqueous polyvinyl alcohol having beensaturated with 30 g of ethyl acetate stirring at 300 rpm.

Once the embryonic microparticles have stabilized, the contents of thereaction flask are transferred to 50 liters of water stirring in a60-liter stainless-steel beaker at 12° C. After having stirred ininitial wash for approximately 15 minutes, the hardened microparticlesare wet-sieved onto a 25-micron sieve. The product retained by the sieveis transferred to a second wash volume of 40 liters of water stirring at12° C. After three hours stirring in second wash, the microparticles areisolated by sieving through a sieve stack composed of 25, 90, 150, 212and 300 micron openings. Each sieve is washed with liberal portions offresh water to more effectively separate the different sizes ofmicroparticles, and the product is allowed to air-dry on sieves.

Example 6 Preparation of 25%-Loaded Zeranol Microparticles

The example describes the preparation of 25%-loaded zeranolmicroparticles with an 85:15 poly (d,l-lactide-co-glycol ide) excipient.

To prepare a 5 g batch of 25%-loaded zeranol microparticles, 1.25 g ofzeranol and 3.75 g of 85:15 dl-PLGA are dissolved in 33.0 g of ethylacetate in an Erlenmeyer flask at 59° C. The drug/polymer solution isadded to a 100-ml jacketed reaction flask containing about 93 g of 5%aqueous polyvinyl alcohol having been saturated with 5 g of ethylacetate at 59° C. and stirring at 300 rpm.

Once the embryonic microparticles had stabilized, the contents of thereaction flask are transferred to 3.5 liters of water stirring in a4-liter beaker at 12° C. After having stirred in the initial wash forapproximately 1/2 hour, the microparticles are wet sieved onto a25-micron sieve. The retained product is transferred to a second wash of3.5 liters of water at 12° C. After 3 hours in the second wash themicroparticles are isolated by sieving through a sieve stack composed of25, 45, 90, 150 and 212 micron pore openings. Each sieve is washed withliberal portions of water to more effectively separate the differentsizes of microparticles, and the product is allowed to air dry onsieves.

Example 7 Preparation of 50%-Loaded Zeranol Microparticles

This example describes the preparation of 50%-loaded zeranolmicroparticles with a poly (d,l-lactide) excipient.

To prepare a 5 g batch of 50%-loaded zeranol microparticles 2.5 g ofzeranol and 2.7 g of dl-PLA, dissolved in 63 g of ethyl acetate in anErlenmeyer flask at 59° C. The drug/polymer solution is added to a 100ml jacketed reaction flask containing about 90 g of 3% aqueous polyvinylalcohol, having been saturated with 6 g of ethyl acetate at 58° C. andstirring at 200 rpm.

Once the embryonic microparticles have stabilized, the contents of thereaction flask are transferred to 4 liters of water stirring in a4-liter beaker at 12° C. After having stirred in the initial wash for 23minutes, the microparticles are wet sieved onto a 25-micron sieve. Theproduct retained by the sieve is transferred to a second wash of 4liters stirring at 90° C. After stirring for three hours in a secondwash, the microparticles are isolated by sieving through a sieve stackcomposed of 25, 45, 90, 150 and 212 micron pore openings. Each sieve iswashed with liberal portions of water, and the product is allowed to airdry on sieves.

Example 8 Effect of Injectable Microparticle Formulation on PromotingWeight Gain in Beef Cattle

Estradiol benzoate microparticles prepared by the methods describedabove were tested in beef calves to determine the effect on weight gain.Three groups of 22 calves each were used. An untreated control groups,T1, a test group T5, and a positive control group, T6. The test group(T5), received injections of 15 mg of estradiol benzoatemicroencapsulated in poly(lactide-co-glycolide excipient. The positivecontrols (T6) received the commercial implant Ralgro (zeranol active) 36mg. The Hereford calves weighed less than 250 lbs at the time oftreatment and the three groups were comprised of 10 male and 12 femaleanimals per group. All calves remained with their dams during the168-day study and then they were weaned. Calves were weighted, treatmentsite inspected, and other general health observations made at 28-dayintervals. Animals were weighted on a portable Paul cattle scaleequipped with a digital readout. The results of the study are shown inTables I and II. The biodegradable microparticles were more effectivethan the commercial implants in increasing the weight of the animalsduring the treatment period.

                  TABLE 1                                                         ______________________________________                                        EFFECT OF INJECTABLE MICROPARTICLES                                           ON GROWTH OF HEREFORD BEEF CALVES                                                        Daily           Daily                                                         Gain at                                                                              Gain     Gain at  Gain                                                 Day 140                                                                              Over     Day 168  Over                                                 (lbs)  Control  (lbs)    Control                                   ______________________________________                                        TI           1.66     --       1.62   --                                      Untreated Control                                                             T5           1.86      (12%)   1.82   (12.3%)                                 Estrogen                                                                      Microspheres                                                                  T6           1.73     (4.2%)   1.70    (4.9%)                                 Ralgro                                                                        Estrogen              7.5%            7.1%                                    Microparticles        increase        increase                                vs. Ralgro                                                                    ______________________________________                                    

                                      TABLE II                                    __________________________________________________________________________    Weight Gain of Hereford Calves Treated with biodegradable microspheres        Calf     Day 0 Wts.                                                                             D28 D56 D84 D112                                                                              Day 140 Wts                                                                            Day 168 Wts                                                                             Total                    Trt.                                                                             I.D.                                                                             Sex                                                                              1st                                                                              2nd                                                                              Avg.                                                                             WT  WT  WT  WT  1st                                                                              2nd                                                                              Avg.                                                                             1st 2nd                                                                              Avg.                                                                             Gain                     __________________________________________________________________________    T5 11 H  155                                                                              149                                                                              152                                                                              196 238 312 360 417                                                                              418                                                                              418                                                                              464 468                                                                              466                                                                              314                         24 H  159                                                                              150                                                                              155                                                                              189 220 295 330 412                                                                              403                                                                              408                                                                              447 452                                                                              450                                                                              295                         25 H  131                                                                              124                                                                              128                                                                              169 216 288 312 399                                                                              404                                                                              402                                                                              459 461                                                                              460                                                                              333                         31 H  185                                                                              178                                                                              182                                                                              208 258 335 405 492                                                                              484                                                                              488                                                                              536 540                                                                              538                                                                              357                         32 H  223                                                                              216                                                                              220                                                                              263 312 388 431 508                                                                              494                                                                              501                                                                              545 550                                                                              548                                                                              328                         50 H  151                                                                              144                                                                              148                                                                              176 214 286 317 399                                                                              386                                                                              393                                                                              420 431                                                                              426                                                                              278                         54 H  169                                                                              172                                                                              171                                                                              197 235 325 375 452                                                                              454                                                                              453                                                                              499 503                                                                              501                                                                              331                         103                                                                              H  148                                                                              140                                                                              144                                                                              189 236 309 363 467                                                                              435                                                                              451                                                                              475 486                                                                              481                                                                              337                         109                                                                              H  176                                                                              169                                    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                          423                                                                              261                         127                                                                              H  146                                                                              141                                                                              144                                                                              174 204 274 317 384                                                                              375                                                                              380                                                                              428 434                                                                              431                                                                              288                         29 S  154                                                                              150                                                                              152                                                                              185 214 283 324 421                                                                              377                                                                              399                                                                              435 444                                                                              440                                                                              288                         33 S  180                                                                              173                                                                              177                                                                              205 256 343 404 491                                                                              480                                                                              486                                                                              526 532                                                                              529                                                                              353                         34 S  150                                                                              144                                                                              147                                                                              181 226 299 347 433                                                                              411                                                                              422                                                                              459 459                                                                              459                                                                              312                         57 S  186                                                                              180                                                                              183                                                                              217 255 333 375 462                                                                              443                                                                              453                                                                              504 495                                                                              500                                                                              317                         63 S  119                                                                              115                                                                              117                                                                              148 180 248 281 375                                                                              335                                                                              355                                                                              389 390                                                                              390                                                                              273                         80 S  168                                                                              165                                                                              167                                                                              197 237 314 359 434                                                                              420                                                                              427                                                                              486 498                                                                              492                                                                              326                         84 S  135                                                                              131                                                                              133                                                                              158 180 218 260 322                                                                              309                                                                              316                                                                              360 365                                                                              363                                                                              230                         85 S  192                                                                              195                                                                              194                                                                              226 268 346 387 479                                                                              432                                                                              456                                                                              504 508                                                                              506                                                                              313                         116                                                                              S  160                                                                              147                                                                              154                                                                              190 224 296 347 433                                                                              418                                                                              426                                                                              467 478                                                                              473                                                                              319                         121                                                                              S  206                                                                              196                                                                              201                                                                              241 279 348 394 462                                                                              459                                                                              461                                                                              508 496                                                                              502                                                                              301                      T6 1  H  160                                                                              149                                                                              155                                                                              182 205 273 327 401                                                                              396                                                                              399                                                                              449 442                                                                              446                                                                              291                         2  H  179                                                                              172                                                                              176                                                                              208 257 329 362 467                                                                              436                                                                              452                                                                              477 486                                                                              482                                                                              306                         46 H  174                                                                              176                                                                              175                                                                              202 234 305 355 411                                                                              414                                                                              413                                                                              452 455                                                                              454                                                                              279                         64 H  147                                                                              140                                                                              144                                                                              181 220 286 327 383                                                                              373                                                                              378                                                                              436 426                                                                              431                                                                              288                         66 H  127                                                                              122                                                                              125                                                                              164 202 274 329 413                                                                              391                                                                              402                                                                              454 460                                                                              457                                                                              333                         73 H  150                                                                              144                                                                              147                                                                              186 197 262 330 368                                                                              344                                                                              356                                                                              398 385                                                                              392                                                                              245                         92 H  193                                                                              190                                                                              192                                                                              223 260 333 347 447                                                                              433                                                                              440                                                                              498 493                                                                              496                                                                              304                         106                                                                              H  166                                                                              158                                                                              162                                                                              192 224 252 308 399                                                                              357                                                                              378                                                                              408 416                                                                              412                                                                              250                         131                                                                              H  139                                                                              134                                                                              137                                                                              169 199 264 311 396                                                                              361                                                                              379                                                                              414 396                                                                              405                                                                              269                         132                                                                              H  152                                                                              147                                                                              150                                                                              184 219 299 324 392                                                                              394                                                                              393                                                                              439 419                                                                              429                                                                              280                         139                                                                              H  103                                                                              98 101                                                                              127 155 215 258 278                                                                              276                                                                              277                                                                              336 326                                                                              331                                                                              231                         140                                                                              H  155                                                                              149                                                                              152                                                                              172 209 272 309 404                                                                              378                                                                              391                                                                              414 403                                                                              409                                                                              257                         12 S  131                                                                              131                                                                              131                                                                              160 197 257 300 367                                                                              355                                                                              361                                                                              403 415                                                                              409                                                                              278                         13 S  182                                                                              180                                                                              181                                                                              207 241 305 350 426                                                                              412                                                                              419                                                                              470 477                                                                              474                                                                              293                         16 S  159                                                                              154                                                                              157                                                                              186 233 299 344 429                                                                              422                                                                              426                                                                              475 478                                                                              477                                                                              320                         28 S  143                                                                              137                                                                              140                                                                              N.W.                                                                              197 254 306 406                                                                              364                                                                              385                                                                              429 428                                                                              429                                                                              289                         40 S  111                                                                              107                                                                              109                                                                              138 167 224 270 378                                                                              337                                                                              358                                                                              400 405                                                                              403                                                                              294                         56 S  172                                                                              163                                                                              168                                                                              194 220 272 308 382                                                                              379                                                                              381                                                                              422 413                                                                              418                                                                              250                         61 S  167                                                                              164                                                                              166                                                                              196 230 298 324 389                                                                              384                                                                              387                                                                              434 442                                                                              438                                                                              273                         70 S  188                                                                              188                                                                              188                                                                              207 247 311 374 468                                                                              449                                                                              459                                                                              516 522                                                                              519                                                                              331                         112                                                                              S  198                                                                              188                                                                              193                                                                              223 265 349 408 492                                                                              474                                                                              483                                                                              542 536                                                                              539                                                                              346                         119                                                                              S  151                                                                              144                                                                              148                                                                              178 212 279 306 418                                                                              382                                                                              400                                                                              424 424                                                                              424                                                                              277                      T1 18 H  151                                                                              149                                                                              150                                                                              180 209 270 328 422                                                                              394                                                                              408                                                                              439 443                                                                              441                                                                              291                         19 H  167                                                                              161                                                                              164                                                                              193 228 289 334 391                                                                              385                                                                              388                                                                              434 411                                                                              423                                                                              259                         37 H  158                                                                              159                                                                              159                                                                              184 219 292 330 390                                                                              388                                                                              389                                                                              426 413                                                                              420                                                                              261                         38 H  143                                                                              135                                                                              139                                                                              167 202 278 326 404                                                                              417                                                                              411                                                                              456 442                                                                              449                                                                              310                         69 H  113                                                                              106                                                                              110                                                                              143 172 232 269 335                                                                              327                                                                              331                                                                              388 388                                                                              388                                                                              279                         78 H  147                                                                              149                                                                              148                                                                              178 216 288 332 397                                                                              398                                                                              398                                                                              442 445                                                                              444                                                                              296                         98 H  163                                                                              160                                                                              162                                                                              197 235 297 324 423                                                                              391                                                                              407                                                                              431 423                                                                              427                                                                              266                         99 H  154                                                                              147                                                                              151                                                                              177 221 279 312 373                                                                              377                                                                              375                                                                              413 418                                                                              416                                                                              265                         102                                                                              H  222                                                                              215                                                                              219                                                                              250 301 388 414 503                                                                              500                                                                              502                                                                              544 544                                                                              544                                                                              326                         123                                                                              H  182                                                                              172                                                                              177                                                                              205 238 300 339 432                                                                              390                                                                              411                                                                              437 446                                                                              442                                                                              265                         126                                                                              H  175                                                                              168                                                                              172                                                                              200 232 307 357 418                                                                              413                                                                              416                                                                              454 442                                                                              448                                                                              277                         135                                                                              H  130                                                                              130                                                                              130                                                                              154 182 241 280 346                                                                              346                                                                              346                                                                              388 384                                                                              386                                                                              256                         9  S  202                                                                              201                                                                              202                                                                              230 269 335 381 477                                                                              443                                                                              460                                                                              488 508                                                                              498                                                                              297                         17 S  135                                                                              132                                                                              134                                                                              158 192 251 291 354                                                                              360                                                                              357                                                                              409 407                                                                              408                                                                              275                         21 S  168                                                                              158                                                                              163                                                                              192 223 294 335 414                                                                              388                                                                              401                                                                              426 434                                                                              430                                                                              267                         26 S  152                                                                              147                                                                              150                                                                              176 196 252 290 357                                                                              352                                                                              355                                                                              393 394                                                                              394                                                                              244                         47 S  160                                                                              158                                                                              159                                                                              184 205 277 307 359                                                                              365                                                                              362                                                                              405 408                                                                              407                                                                              248                         52 S  146                                                                              139                                                                              143                                                                              N.W.                                                                              189 244 296 350                                                                              345                                                                              348                                                                              397 401                                                                              399                                                                              257                         68 S  117                                                                              114                                                                              116                                                                              141 160 217 263 341                                                                              321                                                                              331                                                                              389 393                                                                              391                                                                              276                         101                                                                              S  183                                                                              180                                                                              182                                                                              198 235 306 359 413                                                                              405                                                                              409                                                                              455 460                                                                              458                                                                              276                         111                                                                              S  189                                                                              182                                                                              186                                                                              212 241 313 356 438                                                                              423                                                                              431                                                                              472 462                                                                              467                                                                              282                         137                                                                              S  177                                                                              169                                                                              173                                                                              198 219 286 315 412                                                                              374                                                                              393                                                                              403 390                                                                              397                                                                              224                      __________________________________________________________________________

Example 9 Duration of Delivery of the Active Agent--Use of a Mixture of20%- and 30%-Loaded Microparticles to Deliver Estradiol Benzoate

Two batches, 20% loaded and 30% loaded, of estradiol benzoatemicroparticles were formulated in an 80/20 blend (by weight and tested)and tested in 6 Holstein bull calves to determine serum estradiollevels. Calves weighing between 92 and 116 pounds at the time oftreatment were injected in the ear (3 calves) and in the leg muscle (3calves) with the test material. A dose of 40 mg of estradiol benzoate(plus slight excess to offset syringe retention) microencapsulated in an85:15 lactide:glycolide copolymer was given as a 1 cc suspension. Thesuspending fluid was a 2% aqueous solution of carboxymethyl cellulosewith 1% tween 20 surfactant. Serum samples were collected forapproximately 130 days. The results are shown in Table III, and FIG. 1.These serum estradiol levels correlated well with actual animal weightgain demonstrated when the efficacy of this product was tested in a feedlot trial. This particular combination of steroid and polymericexcipient provided efficacious levels of estradiol in the animals for168 days.

                  TABLE III                                                       ______________________________________                                        Estradiol Levels                                                                           SR052-26B SR052-26B                                                           Muscle    Ear                                                    Days         (pg/ml)   (pg/ml)                                                ______________________________________                                        -7           10         4                                                     -5            6         2                                                     -3           19         10                                                     0            6         4                                                      1           42        113                                                     3           19         51                                                     7           10         35                                                     10          17        178                                                     14          84         67                                                     17          56        422                                                     21          96        172                                                     24          95        326                                                     29          114       514                                                     31          105       762                                                     36          72        532                                                     38          75        667                                                     42          35        373                                                     45          22        318                                                     49          19        112                                                     52          26         81                                                     56          35        134                                                     59          44        104                                                     63          62         93                                                     66          87        335                                                     70          79        332                                                     73          56        445                                                     77          61        497                                                     80          39        225                                                     84          37        163                                                     87          52        151                                                     91          38        321                                                     94          28        244                                                     98          15        311                                                    101          16        105                                                    105          12        122                                                    108          14        114                                                    112          20         46                                                    115          13         58                                                    119          20         29                                                    122          21         25                                                    129          24         24                                                    ______________________________________                                    

Example 10 Duration of Delivery of the Active Agent--Use of a Mixture of15%- and 30%-Loaded Microparticles to Deliver Estradiol Benzoate

Poly(d,l-lactide) was used to microencapsulate estradiol benzoate andthe resulting product was administered to 6 Holstein calves to evaluateserum estradiol levels. Two batches, 15% and 30% loaded, were blended toafford the test material. The calves weighing between 101 and 145pounds, were treated with 40 mg of microencapsulated estradiol benzoateintramuscularly at the base of the ear. The microparticles weresuspended in an aqueous carboxymethylcellulose/tween 20 solution. Serumsamples were collected at approximately 4-day intervals over a period ofseveral months. The resulting data (Table IV) show that thebiodegradable microparticles released the active agent for 200 days inthe animals.

                  TABLE IV                                                        ______________________________________                                        Estradiol Levels                                                                           SR046-120                                                                     Ear                                                                     Day   (pg/ml)                                                          ______________________________________                                               -4    14.0                                                                     0    14.5                                                                     1    40.9                                                                     2    25.0                                                                     3    22.7                                                                     4    58.0                                                                     5    27.7                                                                     7    24.8                                                                     10   14.7                                                                     14   37.9                                                                     17   28.4                                                                     21   82.0                                                                     24   63.6                                                                     28   198.0                                                                    31   189.8                                                                    35   85.6                                                                     38   334.1                                                                    42   195.2                                                                    45   186.2                                                                    49   160.9                                                                    52   100.3                                                                    56   117.5                                                                    59   70.5                                                                     63   49.5                                                                     67   40.2                                                                     70   21.5                                                                     74   22.6                                                                     77   28.8                                                                     80   100.4                                                                    84   10.3                                                                     87   28.0                                                                     91   18.6                                                                     94   47.8                                                                     98   33.2                                                                    101   32.6                                                                    105   57.7                                                                    108   71.3                                                                    112   88.9                                                                    115   91.5                                                                    119   109.0                                                                   122   189.7                                                                   126   132.6                                                                   129   352.5                                                                   133   366.4                                                                   136   106.1                                                                   140   105.7                                                                   143   107.4                                                                   147   126.7                                                                   150   92.7                                                                    154   118.9                                                                   157   100.3                                                                   161   69.5                                                                    168   58.9                                                                    175   34.8                                                                    182   51.0                                                                    189   22.9                                                                    196   19.1                                                                    203   16.5                                                             ______________________________________                                    

Example 11 Duration of Delivery of the Active Agent--Use of a Mixture of30%- and 50%-Loaded Microparticles to Deliver Trenbolone Acetate

Trenbolone acetate was microencapsulated in an 85:15 copolymer of lacticand glycolic acids, and the resulting product evaluated in 6 Holsteinbull calves. The formulation tested was a 50/50 blend of a 30% loadedbatch and a 50% loaded batch. Calves weighing between 91 and 117 poundswere injected either i.m. in the leg (3 calves) or at the base of theear (3 calves) with 200 mg of encapsulated trenbolone acetate. Themicroparticles were suspended in an aqueous carboxymethylcellulose/tween20 injection vehicle. Serum samples were collected and analyzed fortrenbolone acetate at selected intervals. Table V shows that elevatedserum drug levels were achieved over the 150-day test period. Thisformulation was shown to be efficacious in increasing the weight gain ofbeef calves.

                  Table V                                                         ______________________________________                                        Trenbolone acetate levels                                                                  SR046-100 SR046-100                                                           Ear       Muscle                                                 Days         (pg/ml)   (pg/ml)                                                ______________________________________                                        -4            39        13                                                    -1            13        24                                                     0            26        47                                                     1           300       183                                                     2           202       104                                                     3           269        91                                                     4           233       135                                                     5           290       124                                                     7           295       147                                                     10          156       128                                                     14          146        92                                                     17          300        91                                                     21          272        88                                                     24          145        62                                                     28          130        30                                                     31          141        94                                                     35          318        43                                                     38          285       150                                                     42          219       222                                                     45          466       295                                                     49          517       231                                                     52          349       128                                                     56          273       129                                                     59           77       120                                                     63           83        86                                                     66          268        77                                                     70          106        81                                                     73           66        49                                                     77          206       113                                                     80          130       111                                                     84          151       125                                                     87          113       107                                                     91          105        84                                                     94           68       101                                                     98           61        65                                                    101           89        69                                                    105          108        57                                                    108            46       90                                                    112          103        79                                                    115          140        83                                                    119          115        68                                                    122           97       122                                                    129           18       122                                                    136           53        78                                                    143           35        73                                                    150           35        50                                                    ______________________________________                                    

Having now fully described the invention, it will be understood by thosewith skill in the art that the scope may be performed within a wide andequivalent range of conditions, parameters and the like, withoutaffecting the spirit or scope of the invention or any embodimentthereof.

What is claimed is:
 1. An injectable composition comprisingmicroparticles, wherein said microparticles comprise a biodegradablepolymeric matrix, wherein said composition comprises two or more steroidgrowth promoters, wherein each of said steroid growth promoters isseparately microencapsulated in said polymeric matrix such that each ofsaid microparticles contains a single steroid growth promoter, andwherein the polymeric matrix of said microparticle composition isselected from the group consisting of poly-d,l-lactic acid,poly-L-lactic acid, polyglycolic acid, copolymers of mixed d,l-lacticacid and glycolic acid, copolymers of L-lactic acid and glycolic acid,copolyoxylates, polycaprolactone, poly(lactic acid-caprolactone),poly(glycolic acid-caprolactone), casein, albumin, and waxes.
 2. Aninjectable composition comprising microparticles, wherein saidmicroparticles comprise a biodegradable polymeric matrix, wherein saidcomposition comprises two or more steroid growth promoters, wherein eachof said steroid growth promoters is separately microencapsulated in saidpolymeric matrix such that each of said microparticles contains a singlesteroid growth promoter, and wherein said microparticles are loaded with1 to 75 wt. % of said growth promoter based on the weight of saidpolymeric matrix.
 3. An injectable composition comprisingmicroparticles, wherein said microparticles comprise a biodegradablepolymeric matrix, wherein said composition comprises two or more steroidgrowth promoters, wherein each of said steroid growth promoters isseparately microencapsulated in said polymeric matrix such that each ofsaid microparticles contains a single steroid growth promoter, andwherein said microparticles range in size from submicron to 500μ.
 4. Aninjectable composition comprising microparticles, wherein saidmicroparticles comprise a biodegradable polymeric matrix, wherein saidcomposition comprises two or more steroid growth promoters, wherein eachof said steroid growth promoters is separately microencapsulated in saidpolymeric matrix such that each of said microparticles contains a singlesteroid growth promoter, and wherein said microparticle composition isin a liquid injection vehicle.
 5. An injectable composition comprisingmicroparticles, wherein said microparticles comprise a biodegradablepolymeric matrix, wherein said composition comprises two or more steroidgrowth promoters, wherein each of said steroid growth promoters isseparately microencapsulated in said polymeric matrix such that each ofsaid microparticles contains a single steroid growth promoter, whereinsaid microparticle composition is in a liquid injection vehicle, andwherein said liquid injection vehicle is selected from the groupconsisting of physiological saline solution, and an aqueous solution ofcarboxymethylcellulose with a surfactant.
 6. An injectable compositioncomprising microparticles, wherein said microparticles comprise abiodegradable polymeric matrix, wherein said composition comprises twoor more steroid growth promoters, wherein each of said steroid growthpromoters is separately microencapsulated in said polymeric matrix suchthat each of said microparticles contains a single steroid growthpromoter, and wherein said microparticles are administered byintramuscular injection.
 7. An injectable composition comprisingmicroparticles, wherein said microparticles comprise a biodegradablepolymeric matrix, wherein said composition comprises two or more steroidgrowth promoters, wherein all of said steroid growth promoters areco-microencapsulated in said polymeric matrix such that all of saidmicroparticles contain all of said steroid growth promoters, and whereinthe polymeric matrix of said microparticle composition is selected fromthe group consisting of poly-d,l-lactic acid, poly-L-lactic acid,polyglycolic acid, copolymers of mixed d,l-lactic acid and glycolicacid, copolymers of L-lactic acid and glycolic acid, copolyoxylates,polycaprolactone, poly(lactic acid-caprolactone), poly(glycolicacid-caprolactone), casein, albumin, and waxes.
 8. An injectablecomposition comprising microparticles, wherein said microparticlescomprise a biodegradable polymeric matrix, wherein said compositioncomprises two or more steroid growth promoters, wherein all of saidsteroid growth promoters are co-microencapsulated in said polymericmatrix such that all of said microparticles contain all of said steroidgrowth promoters, and wherein said microparticles are loaded with 1 to75 wt. % of said growth promoter based on the weight of said polymericmatrix.
 9. An injectable composition comprising microparticles, whereinsaid microparticles comprise a biodegradable polymeric matrix, whereinsaid composition comprises two or more steroid growth promoters, whereinall of said steroid growth promoters are co-microencapsulated in saidpolymeric matrix such that all of said microparticles contain all ofsaid steroid growth promoters, and wherein said microparticles range insize from submicron to 500μ.
 10. An injectable composition comprisingmicroparticles, wherein said microparticles comprise a biodegradablepolymeric matrix, wherein said composition comprises two or more steroidgrowth promoters, wherein all of said steroid growth promoters areco-microencapsulated in said polymeric matrix such that all of saidmicroparticles contain all of said steroid growth promoters, and whereinsaid microparticle composition is in a liquid injection vehicle.
 11. Aninjectable composition comprising microparticles, wherein saidmicroparticles comprise a biodegradable polymeric matrix, wherein saidcomposition comprises two or more steroid growth promoters, wherein allof said steroid growth promoters are co-microencapsulated in saidpolymeric matrix such that all of said microparticles contain all ofsaid steroid growth promoters, wherein said microparticle composition isin a liquid injection vehicle, and wherein said liquid injection vehicleis selected from the group consisting of physiological saline solutionand an aqueous solution of carboxymethylcellulose with a surfactant. 12.An injectable composition comprising microparticles, wherein saidmicroparticles comprise a biodegradable polymeric matrix, wherein saidcomposition comprises two or more steroid growth promoters, wherein allof said steroid growth promoters are co-microencapsulated in saidpolymeric matrix such that all of said microparticles contain all ofsaid steroid growth promoters, and wherein said microparticles areadministered by intramuscular injection.
 13. The composition of any ofclaims 1-12, wherein said growth promoters are selected from the groupconsisting of 17β-estradiol, estradiol benzoate, trenbolone acetate,zeranol, and testosterone.
 14. The composition of claim 13 wherein saidcombination comprises any two of the growth promoters of claim
 13. 15.The composition of claim 13 wherein said combination comprises zeranoland estradiol benzoate.
 16. The composition of claim 13 wherein saidcombination comprises zeranol and 17β-estradiol.
 17. The composition ofclaim 13 wherein said combination comprises zeranol and testosterone.18. The composition of claim 13 wherein said combination comprisestrenbolone acetate and estradiol benzoate.
 19. The composition of claim13 wherein said combination comprises trenbolone acetate and17β-estradiol.
 20. The composition of claim 13 wherein said combinationcomprises 17β-estradiol and estradiol benzoate.
 21. The composition ofclaim 13 wherein said combination comprises 17β-estradiol andtestosterone.
 22. The composition of claim 13 wherein said combinationcomprises estradiol benzoate and testosterone.
 23. The composition ofclaim 13 wherein said combination comprises testosterone and trenboloneacetate.
 24. The composition of claim 13 wherein said combinationcomprises zeranol and trenbolone acetate.
 25. The composition of any ofclaims 1-5 or 7-11, wherein said composition is administered bysubcutaneous injection.